Role of peroxisome proliferator-activated receptor alpha (PPARα) and PPARα-mediated species differences in triclosan-induced liver toxicity

Triclosan, a widely used broad spectrum anti-bacterial agent, is hepatotoxic in rodents and exhibits differential effects on mouse and human peroxisome proliferator-activated receptor alpha (PPAR) in vitro; however, the mechanism underlying triclosan-induced liver toxicity has not been elucidated. This study examined the role of mouse and human PPAR in triclosan-induced liver toxicity by comparing the effects between wild-type and PPAR-humanized mice. Female mice of each genotype received dermal applications of 0, 58, or 125mg triclosan/kg body weight daily for 13 weeks. Following the treatment, triclosan caused an increase in liver weight and relative liver weight only in wild-type mice. The expression levels of PPAR target genes cytochrome P450 4A and acyl-coenzyme A oxidase 1 were increased in livers of both wild-type and PPAR-humanized mice, indicating that triclosanactivated PPAR. Triclosan also elevated the expression levels of peroxisomal membrane protein PMP70 and catalase in the livers of both genotypes, suggesting that triclosan promoted the production of hepatocyte peroxisomes. There was an enhanced expression of cyclin D1, c-myc, proliferating cell nuclear antigen, and Ki67, and a higher percentage of BrdU-labeled hepatocytes in wild-type mice, but not in PPAR-humanized mice, demonstrating triclosan-activated PPAR had differential effects on the hepatocyte proliferation. These findings imply that the differential effects of triclosan-activated PPAR on cell proliferation may play a role in the species differences in triclosan-induced liver toxicity.